R5 Macrophage-Tropic HIV-1 in the Male Genital Tract

Bednar, Maria M.; Hauser, Blake M.; Li, Ping; Dukhovlinova, Elena; Zhou, Shuntai; Arrildt, Kathryn T.; Hoffman, Irving; Eron, Joseph J.; Cohen, Myron S.; Swanstrom, Ronald

doi:10.1128/jvi.01842-15

Cited by 9 publications

(10 citation statements)

References 21 publications

(26 reference statements)

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“…we were able to sample virus before and shortly after the person started therapy and found that both the standard CD4‐high (T cell‐tropic) and the unexpected CD4‐low (M‐tropic) viruses were reduced equivalently in blood viral load by therapy, indicating both were replicating in short‐lived T cells (Joseph and Swanstrom, unpublished data). Similarly, we have detected M‐tropic virus in the semen of one male . We hypothesize that in each of these cases the M‐tropic virus evolved in an isolated tissue depleted of CD4+ T cells and was introduced into the systemic pool of replicating virus in the former or into draining seminal fluid in the latter.…”

Section: Introductionmentioning

confidence: 63%

“…Similarly, we have detected M-tropic virus in the semen of one male. 61 We hypothesize that in each of these cases the M-tropic virus evolved in an isolated tissue depleted of CD4+ T cells and was introduced into the systemic pool of replicating virus in the former or into draining seminal fluid in the latter.…”

Section: F I G U R E 1 M-tropic Hiv-1 Is Efficient At Entering Cells mentioning

confidence: 99%

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The evolution of HIV-1 entry phenotypes as a guide to changing target cells

Joseph

Swanstrom

2018

Journal of Leukocyte Biology

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Summary Sentence: The R5 T cell-tropic form of HIV-1 is the most abundant form and the evolutionary precursor to X4 T cell-tropic and macrophage-tropic variants. AbstractThrough a twist of fate the most common form of HIV-1, as defined by entry phenotype, was not appreciated until recently. The entry phenotype is closely linked to the target cell and thus to virus-host interactions and pathogenesis. The most abundant form of HIV-1 uses CCR5 as the coreceptor and requires a high density of CD4 for efficient entry, defining its target cell as the CD4+ memory T cell. This is the transmitted form of the virus, the form that is found in the blood, and the form that rebounds from the latent reservoir. When CD4+/CCR5+ T cells become limiting the virus evolves to use alternative target cells to support viral replication. In the CNS, the virus can evolve to use a cell that displays only a low density of CD4, while maintaining the use of CCR5 as the coreceptor. When this evolutionary variant evolves, it must be sustaining its replication in either macrophages or microglial cells, which display only a low density of CD4 relative to that on T cells. In the blood and lymphoid system, the major switch late in disease is from T cells expressing CD4 and CCR5 to T cells expressing CD4 and CXCR4, with a change in coreceptor specificity. Thus the virus responds in two different ways to different environments when its preferred target cell becomes limiting.

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Section: Introductionmentioning

confidence: 63%

Section: F I G U R E 1 M-tropic Hiv-1 Is Efficient At Entering Cells mentioning

confidence: 99%

The evolution of HIV-1 entry phenotypes as a guide to changing target cells

Joseph

Swanstrom

2018

Journal of Leukocyte Biology

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“…Unlike CD4 + T cells, macrophages have low levels of surface CD4 and have mostly been observed in the central nervous system of infected patients [184, 185], late in disease [186] and more recently in the male genital compartment [187]. Probably the most well studied compartment as far as macrophage tropism is the central nervous system which has 4 types of macrophages; microglia, meningeal macrophages, perivascular macrophages and macrophages of the choroid-plexus [188].…”

Section: Traits Reported To Be Different Between Transmitted/founder mentioning

confidence: 99%

The HIV-1 transmission bottleneck

et al. 2017

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It is well established that most new systemic infections of HIV-1 can be traced back to one or a limited number of founder viruses. Usually, these founders are more closely related to minor HIV-1 populations in the blood of the presumed donor than to more abundant lineages. This has led to the widely accepted idea that transmission selects for viral characteristics that facilitate crossing the mucosal barrier of the recipient’s genital tract, although the specific selective forces or advantages are not completely defined. However, there are other steps along the way to becoming a founder virus at which selection may occur. These steps include the transition from the donor’s general circulation to the genital tract compartment, survival within the transmission fluid, and establishment of a nascent stable local infection in the recipient’s genital tract. Finally, there is the possibility that important narrowing events may also occur during establishment of systemic infection. This is suggested by the surprising observation that the number of founder viruses detected after transmission in intravenous drug users is also limited. Although some of these steps may be heavily selective, others may result mostly in a stochastic narrowing of the available founder pool. Collectively, they shape the initial infection in each recipient.

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“…However, viruses that have been replicating independently in anatomically distinct regions such as the central nervous system where CD4+ T cells are less abundant, can evolve the ability to enter cells expressing lower densities of CD4, such as macrophages. This has been observed for compartmentalized lineages derived from both the CNS (27) and, in one case, the male genital tract (28). In order to determine whether compartmentalized, semen-derived lineages from our cohort have the ability to enter cells expressing a low density of CD4, we performed SGA of full-length HIV-1 env genes using viral RNA as the template for cDNA synthesis followed by PCR done at template end-point dilution.…”

Section: Resultsmentioning

confidence: 72%

“…Our observation that inflammation does not alter the frequency with which we detect semen-specific HIV-1 lineages suggests that, when compartmentalized lineages are present, they are most likely produced by cells in anatomical areas that are not in direct contact with the periphery. In one extreme case of this type of isolation we previously observed the presence of a macrophage-tropic variant in semen (28) which suggests that in this case there was sufficient depletion of CD4+ T cells, without replenishment, that the virus evolved to expand its target cell specificity. In the current study all of the viruses tested were T cell-tropic, requiring a high density of CD4 for efficient entry into cells.…”

Section: Discussionmentioning

confidence: 89%

Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without STI-associated Urethritis

Zhou

McCann

Hoffman

et al. 2020

Preprint

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AbstractConcurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from ART-naïve men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples full length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of pro-inflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population indicating a recent bottleneck followed by limited viral replication. We documented a case of superinfection where the new strain was restricted to the genital tract. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, where a superinfecting strain can persist, and where specific genotypes can be amplified perhaps initially by cellular proliferation but further by limited viral replication.ImportanceHIV-1 is a sexually transmitted infection that co-exists with other STIs. Here we examine the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.

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R5 Macrophage-Tropic HIV-1 in the Male Genital Tract

Cited by 9 publications

References 21 publications

The evolution of HIV-1 entry phenotypes as a guide to changing target cells

The evolution of HIV-1 entry phenotypes as a guide to changing target cells

The HIV-1 transmission bottleneck

Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without STI-associated Urethritis

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